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Prognostic Factors for High-Risk Early-Stage

Epithelial Ovarian CancerA Gynecologic Oncology Group Study

John K. Chan, MD1

Chunqiao Tian, MS2

Bradley J. Monk, MD3

Thomas Herzog, MD4

Daniel S. Kapp, MD, PhD5

Jeffrey Bell, MD6

Robert C. Young, MD7

1Department of Obstetrics, Gynecology, and

Reproductive Sciences, University of California,

San Francisco School of Medicine, UCSF Helen

Diller Family Comprehensive Cancer Center, San

Francisco, California.

2GOG Statistical & Data Center, Roswell Park

Cancer Institute, Buffalo, New York.

3Department of Obstetrics and Gynecology, Chao

Family Comprehensive Cancer Center, University

of California, Irvine – Medical Center, Orange,

California.

4Department of Obstetrics and Gynecology, Co-

lumbia University, New York, New York.

5Department of Radiation Oncology, Stanford

University School of Medicine, Stanford Cancer

Center, Stanford, California.

BACKGROUND. The purpose was to identify the factors predictive of recurrence

and survival in patients with high-risk (stage I, grade 3; stage IC, stage II, or clear

cell) epithelial ovarian cancer after adjuvant therapy.

METHODS. Data was extracted from patients who underwent primary surgery fol-

lowed by adjuvant therapy in 2 randomized trials by the Gynecologic Oncology

Group (Protocols 95 and 157). Kaplan-Meier survival estimates and Cox propor-

tional hazards model adjusted for covariates were used for analyses.

RESULTS. Of 506 patients (median age 5 56.2 years), 347 (68.6%) had stage I and

159 (31.4%) had stage II cancers. The 5-year recurrence-free (RFS) and overall sur-

vivals (OS) were 75.5% and 81.7%, respectively. On multivariate analysis, older age,

higher stage, higher grade, and malignant cytology were independent prognostic

factors predictive for recurrence and poorer survival. The risk of recurrence was

higher for those 60 versus < 60 years (hazards ratio [HR] 5 1.57, 95% confidence

interval [CI], 1.12–2.19), stage II (stage II: HR 5 2.70, 95% CI, 1.41–5.16) versus

stage IA or IB, grade 2 (HR 5 1.84, 95% CI, 1.04–3.27) and grade 3 (HR 5 2.47, 95%

CI, 1.39–4.37) versus grade 1, and positive versus negative cytology (HR 5 1.72,

95% CI, 1.21–2.45). By using these factors in a prognostic index, those with low-

risk (no or 1 risk factor), intermediate-risk (2 factors), and high-risk (3–4 risk fac-

tors) disease had survivals of 88%, 82%, and 75%, respectively (P < .05).

CONCLUSIONS. Age, stage, grade, and cytology are important prognostic factors in high-risk early-stage epithelial ovarian cancer. This information may be used in the design

of future clinical trials.Cancer 2008;112:2202–10. 2008 American Cancer Society.

KEYWORDS: ovarian cancer, early-stage, prognosis, survival.

6Department of Obstetrics and Gynecology, Ohio

State University, Riverside Methodist Hospital,

Columbus, Ohio.

7Department of Medical Oncology, Fox Chase

Cancer Center, Philadelphia, Pennsylvania.

This study was supported by National Cancer

Institute grants to the Gynecologic Oncology

Group Administrative Office (CA27469), the

Gynecologic Oncology Group Statistical and Data

Center (CA37517), and Gynecologic OncologyGroup new investigator award to JKC.

The following Gynecologic Oncology Group

member institutions participated in this study:

University of Alabama at Birmingham, Oregon

Health Sciences University, Duke University

Medical Center, Abington Memorial Hospital,

University of Rochester Medical Center, Walter

Reed Army Medical Center, Wayne State

University, University of Minnesota Medical

School, University of Southern California at Los

Angeles, University of Mississippi Medical Center,

Colorado Gynecologic Oncology Group P.C.,

University of California at Los Angeles, University

of Pennsylvania Cancer Center, University of

Miami School of Medicine, Milton S. Hershey

Medical Center, Georgetown University Hospital,

University of Cincinnati, University of North

Carolina School of Medicine, University of Iowa

Hospitals and Clinics, University of Texas

Southwestern Medical Center at Dallas, Indiana

University School of Medicine, Wake Forest

University School of Medicine, Albany Medical

College, University of California Medical Center at

Irvine, Tufts-New England Medical Center, Rush-

Presbyterian-St. Luke’s Medical Center, SUNY

Downstate Medical Center, University of

Kentucky, Eastern Virginia Medical School, The

Cleveland Clinic Foundation, Johns Hopkins

Oncology Center, State University of New York at

Stony Brook, Eastern Pennsylvania GYN/ONC

Center, P.C., Southwestern Oncology Group,

Washington University School of Medicine,

Cooper Hospital/University Medical Center,

Columbus Cancer Council, North Central

Cancer Treatment Group, University of Massa-

chusetts Medical School, Fox Chase Cancer

Center, Medical University of South Carolina,

Women’s Cancer Center, University of Oklahoma,

University of Chicago, and Tacoma General

Hospital.

Address for reprints: John K. Chan, MD, Department

of Obstetrics, Gynecology, and Reproductive Sciences,

University of California, San Francisco School of

Medicine, UCSF Helen Diller Family Comprehensive

Cancer Center, 1600 Divisadero St., Box 1702, San

Francisco, CA 94143-1702; Fax: 415-885-3586;

E-mail: chanjohn@ obgyn.ucsf.edu

Received September 25, 2007; revision received

November 9, 2007; accepted November 19, 2007.

ª 2008 American Cancer SocietyDOI 10.1002/cncr.23390Published online 17 March 2008 in Wiley InterScience (www.interscience.wiley.com).

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I n 2006 there will be an estimated 20,180 new epithelial ovarian cancers diagnosed in the US, with approximately one-third having FIGO (Interna-

tional Federation of Obstetrics and Gynecology) stage

I and II disease.1 Although the survival of early-stage

disease is significantly higher than those with ad-vanced cancers, approximately 20% to 30% of these

patients will die of their disease.2–7

The clinical and pathologic prognostic factors

that have been previously described for patients with

early-stage epithelial ovarian cancers include: age,

stage, tumor rupture, cell type, tumor grade, large

volume ascites, and dense adhesions.8–16 The limita-

tions of many of these prior studies include the small

sample size, inadequacy of surgical staging, inclusion

of borderline tumors, stage III cancers with minimal

residual disease, lack of central pathology review,

and variation in adjuvant therapies.

Young et al.10

suggested that women with low-risk cancers, defined as stage IA, IB, grade 1 or 2,

nonclear-cell histologies, do not need further adju-

vant therapy. Patients with high-risk early-stage

epithelial ovarian cancer, defined as stage I, grade 3;

stage IC, stage II, and clear-cell cancers, were felt to

require postsurgical adjuvant treatment. Over the

past 20 years, the Gynecologic Oncology Group

(GOG) has conducted 2 large prospective clinical

trials on this population. Because both clinical trials

had the same eligibility criteria for patient entry,

these studies provide a unique opportunity to inves-

tigate the prognostic factors for high-risk early-stage

ovarian cancer. The results of this analysis can

potentially allow us to assess factors that are predic-

tive for recurrence and survival in these women.

More important, it can help identify subgroups at

significant risk for recurrence after chemotherapy

treatments who may warrant novel therapies and

more aggressive treatment.

MATERIALS AND METHODSIn all, 506 women diagnosed with high-risk early-stage

epithelial ovarian cancer patients enrolled in 2 pro-

spective randomized clinical trials conducted by

the GOG, protocol 95 (n 5 205) and protocol 157

(n 5 301). High-risk early-stage epithelial ovarian can-

cer was defined as stage IA or IB (grade 3), stage IC orII (any grade), and stage I or II clear-cell epithelial

ovarian cancer. Of these, 150 patients with incomplete

staging information were excluded from this analysis.

Patients provided written informed consent consistent

with all federal, state, and local requirements before

enrolling in the protocols. Details regarding eligibility

criteria, treatment, and outcome for each particular

study have been previously published.17,19 On the

basis of the study entry criteria, a complete surgical

staging procedure was required. In summary, all peri-

toneal surfaces, including the undersurfaces of both

diaphragms, serosa, and mesentery, were to be visually

inspected and palpated for evidence of implants. If

there was no evidence of disease beyond the ovary orpelvis, biopsies of the cul-de-sac, vesico uterine perito-

neum, bilateral pelvic side walls, paracolic gutters, and

undersurface of the diaphragm, and sampling of the

pelvic and para-aortic nodes, were to be performed.

All patients who underwent surgical staging were oper-

ated on by gynecologic oncologists mostly from aca-

demic institutions. In addition, all tumors underwent

central pathology review by expert gynecologic oncol-

ogy pathologists.

Baseline performance status before initiating

chemotherapy was defined according to GOG criteria

as: 0 5 normal activity; 1 5 symptomatic, fully am-

bulatory; 2 5

symptomatic, in bed less than 50% of the time. The primary endpoints for both studies

were disease recurrence-free survival (RFS) and over-

all survival (OS). RFS was calculated from the date of

study enrollment to the date of disease recurrence

(confirmed on physical, serologic, or radiologic exam),

or most recent follow-up visit. OS was calculated

from the date of study enrollment to the date of

death regardless of cause or last follow-up.

Kaplan-Meier survival analyses were performed

initially to estimate RFS and OS by each variable, using

a log-rank test to compare the differences in survival

functions. Multivariate analysis was then conducted to

identify the independent prognostic factors as well as

to estimate their effects on RFS and OS adjusted forcovariates. In survival analysis, patients with a GOG

performance status of 1 or 2 were combined because

of comparable associations with prognosis. In addition,

those with suspicious positive washings were consid-

ered positive for cytology. Furthermore, stage I patients

were further divided into 2 subgroups (stage IA/IB and

stage IC). We elected to use a categorical variable for

age, defined as < 60 years versus 60 years old based

on preassessment. Multivariate analysis was conducted

using a stepwise Cox proportional hazards model, stra-

tified by type of treatment to control for potential con-

founding effects of the 2 study protocols and type of

treatment. All statistical tests were 2-tailed with a sig-nificance level set at 5%. Statistical analyses were per-

formed using Statistical Analysis Software (SAS) v. 9.1

(SAS Institute, Cary, NC).

RESULTSOf the 506 patients included in this analysis, the me-

dian age at diagnosis was 56 years (range, 22–88

Stage I-II Prognostic Factors/Chan et al. 2203


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years) (Table 1). The majority (89.1%) of these

patients were white and the remainder were charac-

terized as Black (4%), Hispanic (4.2%), and Others

(2.8%). The baseline GOG performance status of

these women was 0, 1, and 2 in 52.2%, 43.9%, and

4.0%, respectively. All women underwent primary surgery based on GOG standards. In all, 347 (68.6%)

patients had stage I disease, with stage IA in 13.6%,

IB in 2.0%, and 1C in 53.0%; 159 (31.4%) had stage II

cancers with stage IIA in 8.5%, IIB in 5.5%, and IIC

in 17.4%. Histologic cell types were distributed as

follows: clear cell (27.1%), endometrioid (26.5%),

serous (21.3%), mucinous (9.9%), and other cell types

(15.2%). Tumor grades were distributed as: grade 1

(18.8%), grade 2 (25.1%), grade 3 (29.1%), and not

graded (for clear cell) (27.1%). Of all patients, 153

(30.2%) were found to have ascites, and 219 (43.3%)

had tumor rupture found on surgery. On final pathol-

ogy review of all washings and ascites, 148 (29.6%) were cytologically positive (n 5 125) or suspicious

positive (n 5 23). The presence of ascites during sur-

gery was greater in stage IC (33.6%) and stage II

(32.7%) compared with stage IA/IB (13.9%). The pre-

sence of ascites was also associated with positive

cytology: 46.4% of patients with malignant cells cyto-

logically had ascites and 21.8% of patients without

ascites had positive cytology. Furthermore, most

patients with stage IC (61.9%) or mucinous (62.0%)

tumors had tumor rupture at the time of surgery.

Stage of disease was associated with tumor histology

and grade. Patients with mucinous or clear-cell

histologies were more likely to have stage I rather

than stage II disease compared with other histologies(81.0% for clear cell, 94.0% for mucinous vs 67.7%

for other histologies). Univariate analysis of prog-

nostic factors for RFS and OS are demonstrated in

Table 2.

All of the patients on these 2 trials (GOG 157 and

95) were treated with adjuvant platinum-based

chemotherapy or intraperitoneal radioactive chromic

phosphate. Nineteen percent of patients were treated

with intraperitoneal phosphate (32P), 21% with cyclo-

phosphamide/cisplatin (CP), 31% with carboplatin/

paclitaxel (PC) for 3 courses, and 29% with carbopla-

tin/paclitaxel for 6 courses.

With a median follow-up of 98 months (136months for protocol 95 and 92 months for protocol

157), 140 recurrences (28%) and 151 (30%) deaths

were observed. The estimates of RFS and OS by

patient characteristics are shown in Table 2. Overall,

5-year RFS and OS were predicted to be 76% and

82%, respectively. Patients with age 60 years, stage

II, tumor grade 2 or 3, with the presence of ascites or

positive cytology had significantly worse RFS. There

TABLE 1Patient and Clinicopathologic Characteristics (N 5 506)

No. of patients %

Age, y


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is also a suggestion that patients treated by PC and

CP had comparable RFS, but both of them had

improved RFS compared with patients treated by 32P.

Multivariate analysis identified 4 factors (age,

stage, tumor grade, and cytology) independently pre-

dictive of disease recurrence (Table 3). The relative

risk of disease recurrence for patients at age 60

years versus age


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ease, tumor grade, and cytology. Among the prognos-

tic parameters, these independent prognostic factors were used to develop a prognostic index for potential

clinical application. The prognostic model for RFS is

based on the 4 risk factors: age 60 years (vs

age < 60 years), stage II disease (vs stage I disease),

positive cytology (vs negative cytology), and grade 2–

3 tumors or clear cell (vs grade 1 disease). Low-risk

patients were defined as those with no or 1 risk fac-

tor; intermediate-risk patients as those with any 2

risk factors; and high-risk patients as women with

any 3 or 4 risk factors. The 5-year RFS of the low-,

intermediate-, and high-risk groups was estimated to

be 88%, 71%, and 62%, respectively. On the basis of

the number of risk factors, patients in the low-, inter-

mediate-, and high-risk groups had corresponding

OSs of 88%, 82%, and 75% (P < .05) (Fig. 5A,B).

DISCUSSIONEarly-stage ovarian cancer patients constitute a het-

erogeneous group with respect to risk of recurrence

and survival. Prior reports have shown that patients

with early-stage disease have overall survivals ran-

ging from 60% to 100%.1,2,4–6,20 Thus, stratifying this

heterogeneous group of patients can potentially

identify subgroups of high-risk patients for indivi-

dualized novel therapies in an attempt to improve

outcome. Likewise, it is important to identify a low-

risk group that may not require further cytotoxic

treatment. In this current analysis of 506 women

diagnosed with high-risk stage I and II epithelial

ovarian cancer treated on 2 GOG prospective rando-

mized trials, we found that older age, higher stage,

higher grade, and positive cytology are important

prognostic factors for recurrence and survival.

Earlier studies on the prognostic significance of

age in ovarian cancer have been inconclusive.

Although most reports have shown that younger

women are diagnosed with lower-stage and more well-differentiated tumors, and have an improved

outcome compared with older women,21–25 others

have found that age is not an independent prognos-

tic factor after adjusting for stage and grade of dis-

ease.26–28 In addition, because of the low prevalence

of young patients diagnosed with invasive ovarian

cancer, these studies have also been limited by small

numbers of patients, inclusion of low malignant

FIGURE 1. (A) Kaplan-Meier recurrence-free survival by age group

(P 5 .004). (B) Kaplan-Meier overall survival by age group (P < .001).

FIGURE 2. (A) Kaplan-Meier recurrence-free survival by stage (P 5 .001).

(B) Kaplan-Meier overall survival by stage (P 5 .009).

2206 CANCER May 15, 2008 / Volume 112 / Number 10


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potential tumors, germ cell or sex cord stromal

tumors, and unstaged cancers. In a recent analysis of

28,165 patients, Chan et al.28 identified 400 women

who were 60

(older) (57.4%) years of age. Across all stages, very

young women had a significant survival advantage

over the young and older groups, with 5-year dis-

ease-specific survival estimates at 78.7% versus

58.8% and 35.3%, respectively (P < .001). In this cur-

rent analysis of a well-characterized group of early-

stage ovarian cancer patients with long follow-up,

younger age was an independent prognostic factor

for improved survival after controlling for surgery,

stage, grade, adjuvant therapy, and other clinicopath-

ologic factors.Previous studies have also demonstrated that

stage of disease is a prognostic factor in early-stage

ovarian cancers.13,16,29–33 Patients in this current

study with stage I cancers have a 5-year disease-spe-

cific survival of 84% compared with 76% in those

with stage II disease. An analysis on the subgroups

of stage I cancers found that those with stage IA or

IB disease have a survival of 85.9%. Given the excel-

lent outcome of these patients and the potential

toxicities associated with adjuvant chemotherapy,17,18

future studies must be carefully structured to deter-

mine the risk and benefit of cytotoxic chemotherapy

in low-risk disease. However, the outcome for

patients with stage II is significantly poorer, with RFS

and OS of 65.9 and 76.2%, respectively. Prior studies

have included these patients in clinical trials along

with more advanced (stage III and IV) cancers.31,34

Although the survival of stage II patients is poorer

compared with stage I disease, these women still

have a distinct survival advantage over those with

more advanced cancers.

Tumor grade was also found to be an independ-

ent prognostic factor for progression-free and dis-

ease-specific survival in our study. Similarly, Vergoteet al.35 studied a group of 1545 patients with stage I

disease and found that grade of disease was an inde-

pendent prognostic factor associated with disease-

free survival. These findings have also been con-

firmed by other, smaller studies.11,14,16,30,36–44

In this current analysis, malignant cytology was

an independent prognostic factor for increased risk

of recurrence and poorer survival. Early studies have

FIGURE 3. (A) Kaplan-Meier recurrence-free survival by grade of disease

(P 5 .004). (B) Kaplan-Meier overall survival by grade of disease (P 5 .01).

FIGURE 4. (A) Kaplan-Meier recurrence-free survival by cytology

(P < .001). (B) Kaplan-Meier overall survival by cytology (P 5 .01).



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demonstrated that patients with positive washing have

a poorer prognosis.45,46 Creasman and Rutledge47

reported that 60% of 98 patients with ovarian cancer

who underwent surgery had abnormal peritoneal

cytologic specimens. Likewise, a more recent report

also found positive peritoneal washing cytology at

initial surgery in 90 (80.4%) of 112 patients with

ovarian carcinomas.48 Those authors also showed

that positive cytology portends a poorer prognosis.

The prognostic significance of clear-cell histology

compared with other subtypes of epithelial ovarian

cancers remains controversial. In a recent review of 54 studies on ovarian clear-cell carcinoma, Pecta-

sides et al.49 showed that clear-cell cancers have a

significantly poorer survival compared with other

histologic subtypes of epithelial ovarian cancer. In

patients with more advanced stage cancer, the

response rate to platinum-based chemotherapy and

survival were significantly lower than those with se-

rous tumors. However, others have not been able to

find an association between cell type and prognosis

in early-stage disease. Contributing factors for these

conflicting results may include the lack of central

pathology review and intraobserver variabilities on

determining cell type50,51 and various treatment regi-

mens.49 In this current study of early-stage ovariancancer where the majority of patients were uniformly

staged and treated on 2 standardized protocols, we

were unable find a statistically significant survival

difference between clear-cell and other histologies.

Consistent with prior reports, our data did not

reveal that tumor rupture was associated with a

poorer outcome.15,30,39 However, Vergote et al.35

found a deleterious effect of rupture either during or

before surgery on disease-free survival. The interac-

tion between tumor rupture and more early-stage

cancers in our study may have influenced our ability

to determine the true significance of tumor rupture.

One of the shortcomings of our study is that there isa lack of information regarding the time of rupture,

eg, preoperatively or intraoperatively. Some prior stu-

dies have found that preoperative rupture may carry

a worse prognosis compared with intraoperative rup-

ture.14,52 In addition, this current analysis did not

find ascites to be a significant prognostic factor. This

may be explained by the interaction between ascites,

cytology, and stage of disease. For, after adjusting for

these factors, ascites was no longer prognostically

important.

Our study was limited by the potential selection

bias inherent in randomized trials. This study cohort

may comprise a subset of high-risk patients treated

at research centers that may not represent the expe-

rience in the general population. Furthermore, given

that these patients were enrolled in these 2 large

trials ranging from 1986 to 1998, there may exist sig-

nificant differences related to cancer supportive care

and treatment of recurrences over this time period.

Moreover, there was a lack of complete information

regarding the extent of the comprehensive staging

procedures on all patients. In fact, 29.5% of patients

in the GOG 157 trial had incomplete or inadequately

documented surgical staging information.17 It is im-

portant to note that the descriptive statistics and

results of this study were based on a selected group

of patients with high-risk early-stage cancers definedby the eligibility criteria from 2 randomized clinical

trials of the GOG. Thus, in this specific subset of

patients there is a significantly higher proportion

(27.1%) of clear-cell histologies compared with other

cell types. Therefore, these results may not apply to

the overall group of stage I and II patients, particu-

larly those with stage I, grade 1 or 2 disease, and

nonclear-cell type. Although it is important to iden-

FIGURE 5. (A) Kaplan-Meier recurrence-free survival by number of risk

factors (age 60 years, stage II disease, positive cytology, and grade 23

tumors or clear cell). Low-risk: 01 risk factors; mid-risk: 2 risk factors;

high-risk: 34 risk factors (P < .001). (B) Kaplan-Meier overall survival by

number of risk factors (P < .001).



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tify a low-risk group that may not require further

cytotoxic treatment, we are unable to define such a

low-risk group of patients from this report because

all of the women in these clinical trials received ad-

juvant therapy. Thus, a prospective trial designed to

analyze the benefits of adjuvant therapy versus ob-servation is warranted in this low-risk group defined

by this current study.

The strengths of our study include the high

number of patients reported from 2 randomized pro-

spective trials with defined selection criteria and over

80 months of follow-up. Furthermore, these patients

underwent staging by gynecologic oncologists mostly

from academic institutions. In addition, these tumors

underwent central pathology review by expert gyne-

cologic oncology pathologists.

In summary, our findings suggest that age, stage,

grade, and malignant cytology are important prog-

nostic factors in early-stage epithelial ovarian cancer.This information may be considered in the design of

future clinical trials.

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